This is a competitive renewal application of a grant tht has been funded continuously for the past 8 years. During the first 2 years of the current funding period a significant number of accomplishments have been achieved (see Publication List) and much has been learned. The objective for the proposed new work is to synthesize muscariniccholinergic, receptor-binding, high specific-activity radiotracers containing a gamma emitting radionuclide and evaluate these derivatives as receptor binding radiotracers. We have prepared two muscarinic receptor binding radiotracers [R,S-3-Quinuclidinyl-4-iodobenzilate and R,S-3-Quinuclidinyl-4-bromobenzilate[ that have a high affinity for the muscarinic receptor. We wish to pursue the evaluation of these compounds and prepare other compounds with less nonreceptor binding so that we might approach the ideal of performing "in vivo autoradiography". we plan to work toward this goal by producing high specific activity radiotracers, containing radionuclides of optimum nuclear properties and possessing minimal nonreceptor binding and minimal metabolism. In general, we will apply the guidelines used to develop the optimal in vitro radiotracers to the development of in vivo radiotracers. Progress in in vitro receptor studies has been rapid because of the availability of radiotracers that approach the magic bullet, i.e., interact with only the intended receptor. The in vivo use of radiotracers is no doubt more difficult than in vitro studies but certain parallels exist and will be applied to the in vivo situation. The use of I-123, Br-77 and F-18 will give us flexibility in the chemical and nuclear properties of the receptor binding radiotracers. Successful completion of this project will allow the noninvasive determination of the presence or change in concentration of muscarinic cholinergic receptors as a function of disease. It will also produce radiotracers that localize by virtue of a definite biochemical pathway. This is an important criterion in radiopharmaceutical development because it permits extrapolation from animal models to humans.